CN116082302A - Deuterated indazole-pyridine-phenyl-trifluoroethyl tetra-substituted olefin compound and application thereof - Google Patents

Abstract

The invention discloses a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, a pharmaceutical composition and application. The compound shown in the formula I provided by the invention has good therapeutic effect on breast cancer, in particular to breast cancer positive to estrogen receptor.

Description

Deuterated indazole-pyridine-phenyl-trifluoroethyl tetra-substituted olefin compound and application thereof

Technical Field

The invention belongs to the field of innovative pharmaceutical chemistry, and relates to deuterated indazole-pyridine-phenyl-trifluoroethyl tetra-substituted olefins, a pharmaceutical composition and application thereof.

Background

Breast cancer is the most common cancer in women, accounting for 24% of female cancer morbidity and 15% of female cancer mortality. Statistical analysis of cancer in 2018 showed that about 70% of patients expressed the hormone receptor estrogen receptor alpha (erα; encoded by ESR 1) or a downstream target of erα. Erα is a ligand-dependent transcription factor that binds to a specific ligand (female sex steroid hormone 17b estradiol), and this complex binds to the genomic sequence of the Estrogen Receptor Element (ERE) and modulates transcription of the target gene. In addition, ER binds to heat shock proteins Hsp90 and Hsp70 in the absence of ligand, stabilizing the Ligand Binding Domain (LBD) so that it is accessible to the ligand. The ligand ER dissociates from the heat shock protein, resulting in a conformational change in the receptor, allowing dimerization, DNA binding, interaction with coactivators or co-repressors, and modulation of target gene expression. Clinical and preclinical studies have shown that erα plays a key role in the development of the mammary gland. Thus, several types of era-targeted therapies have been developed to treat advanced, metastatic, recurrent breast cancers, including selective estrogen receptor down-regulation (SERD), such as fulvestrant; selective Estrogen Receptor Modulators (SERMs), such as tamoxifen (tamoxifen); and aromatase inhibitors that reduce systemic estrogen levels, such as exemestane. Although these therapies show better efficacy in ER-positive breast cancers, innate and acquired resistance remains a great challenge in treating ER-positive breast cancers. Many drug resistance mechanisms are proposed, (1) erα interacts with other kinases; (2) cell cycle and apoptosis protein dysregulation; (3) erα coactivator or cosuppression factor expression disorder; (4) most important are highly recurrent erα mutations. The highly recurrent erα mutations are enriched in nearly 30% of hormone therapy resistant metastases, causing activation of ligand-independent erα pathways, rendering the tumor partially resistant to existing hormone therapies. Breast cancer containing highly recurrent mutations in erα has a malignant phenotype with a shorter patient survival compared to wild-type ERS1 breast cancer. Currently endocrine therapy is only effective in part of erα mutants, but most endocrine therapy resistant metastases still rely on erα signaling growth/survival, suggesting that erα mutants remain important reasons driving clinical resistance. Therefore, the development of new generation antagonists capable of simultaneously antagonizing both wild-type and mutant erα is of great importance. H3B-6545 is a selective estrogen receptor covalent antagonist with significant antagonistic activity against wild-type and mutant ER. Currently, in the clinical I/II study stage, it is used to treat advanced metastatic ER-positive, HER-negative breast cancer.

Deuterated drugs refer to the replacement of part of the hydrogen atoms in the drug molecule with deuterium. Deuterated drugs generally retain the biological activity and selectivity of the original drug due to the shape and volume of deuterium in the drug molecule, which is similar to hydrogen. Because the C-D bond is more stable than the C-H bond, the C-D bond is less likely to break during the chemical reaction of the deuterated drug, and the half-life period of the deuterated drug is prolonged. Since 2000, deuteration strategies have been widely used in drug research.

Disclosure of Invention

The invention provides a compound shown in a formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, which has the following structure:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ Or R is ₇ Independently selected from the group consisting of hydrogen and deuterium,

at the same time, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ Or R is ₇ At least one of which is deuterium.

In some embodiments, the compound is represented by any one of the following structural formulas:

the invention provides an application of a compound shown in a formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing a selective estrogen receptor covalent antagonist.

In some embodiments, the estrogen is the receptor is estrogen receptor α.

In some embodiments, the estrogen receptor α is a wild-type estrogen receptor α and a mutant estrogen receptor α.

The invention provides application of a compound shown as I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing a medicament for preventing and/or treating cancer.

In some embodiments, the cancer is breast cancer.

In some embodiments, the breast cancer is estrogen receptor positive breast cancer.

In some embodiments, the estrogen receptor positive breast cancer is selected from the group consisting of wild-type estrogen receptor alpha positive breast cancer, mutant estrogen receptor alpha positive breast cancer.

In some embodiments, the cancer is a cancer associated with aberrant estrogen receptor activity.

In some embodiments, the cancer associated with aberrant estrogen receptor activity is selected from the group consisting of cancers associated with aberrant wild-type estrogen receptor alpha activity, cancers associated with aberrant mutant estrogen receptor alpha activity.

The invention provides a pharmaceutical composition, which contains a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and pharmaceutically acceptable carriers or auxiliary materials.

In the pharmaceutical composition, the compound shown in the formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is used in an amount which is effective in treatment.

The invention provides an application of a pharmaceutical composition in preparing a selective estrogen receptor antagonist.

In some embodiments, the estrogen is the receptor is estrogen receptor α.

In some embodiments, the estrogen receptor α is a wild-type estrogen receptor α and a mutant estrogen receptor α.

The invention provides application of a pharmaceutical composition in preparing medicines for preventing and/or treating cancers.

In some embodiments, the cancer is breast cancer.

In some embodiments, the breast cancer is estrogen receptor positive breast cancer.

In some embodiments, the estrogen receptor positive breast cancer is selected from the group consisting of wild-type estrogen receptor alpha positive breast cancer, mutant estrogen receptor alpha positive breast cancer.

In some embodiments, the cancer is a cancer associated with aberrant estrogen receptor activity.

In some embodiments, the cancer associated with aberrant estrogen receptor activity is selected from the group consisting of cancers associated with aberrant wild-type estrogen receptor alpha activity, cancers associated with aberrant mutant estrogen receptor alpha activity.

The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogenphosphates, dihydrogenphosphates, sulfuric acid (forming sulfates or bisulphates), hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, salts of amino acids (such as arginine and the like), and salts of organic acids such as glucuronic acid.

The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

The term "isomer" refers to compounds of the same chemical formula but having different arrangements of atoms.

The term "metabolite" refers to a pharmaceutically active product of a compound of formula I or a salt thereof produced by in vivo metabolism. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain the metabolites thereof.

Identification of metabolites typically occurs by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, in a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion product from urine, blood, or other biological samples. These products are easily separatedSince they are labeled (others are isolated by using antibodies capable of binding to epitopes present in the metabolite). The metabolite structures are determined in a conventional manner, for example by MS, LC/MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. So long as the metabolite products are not otherwise undetectable in vivo, they are useful in assays for therapeutic dosing of the compounds of the invention. The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to give the compound of formula I itself. The prodrugs are preferably administered orally, as hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.

The invention has the positive progress effects that:

(1) The compounds of the present invention have excellent antagonism to wild type and mutant estrogen receptors.

(2) The compound has excellent pharmacokinetic property, obviously improves the oral bioavailability, prolongs the half life and reduces the dosage of single administration.

(3) The compound has good therapeutic effect on breast cancer carrying wild type and mutant estrogen receptors.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

Example 1: synthesis of Compound I-1

Step one: synthesis of Compound b

Compound a (2 g,12.2 mmol) was dissolved in anhydrous DCM (20 mL), placed at 0deg.C, HATU (5.5 g,14 mmol) and TEA (2.6 mL,18 mmol) were added to the above solution and stirred at room temperature for 10min, compound c (9.2 mL,18 mmol) was slowly added to the mixture and stirred at room temperature for 2h. The reaction was quenched with water (20 mL. Times.3), extracted with DCM, the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound b (600 mg, 25%). MS (ESI, m/z): 198 (M) ⁺ +1).

Step two: synthesis of Compound 2

Compound 1 (6.22 g,10 mmol) and DIPEA (5.3 mL,30 mmol) were dissolved in DCM (50 mL), a solution of compound b (1.97 g,10 mmol) in THF (20 mL) was slowly added dropwise to the solution at 0deg.C under nitrogen, and after the dropwise addition was complete, the reaction was transferred to room temperature for 24h. After the reaction was completed, the reaction was quenched with water, extracted with DCM (40 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 2 (3.3 g, 45%). MS (ESI, m/z): 740 (M) ⁺ +1).

Step three: synthesis of Compound I-1

To a solution of compound 2 (740 mg,1 mmol) in methanol (5 mL) was added dropwise a methanol/HC 1 (4M, 2 mL) solution, and after the completion of the addition, the reaction was stirred at room temperature for 5h. After the reaction is completed, the solvent is removed under reduced pressure, methyl tertiary butyl ether is added for pulping, and pumping is carried outThe filter cake was collected to give compound I-1 (471 mg, 85%). 1H NMR (500 mhz, chloroform-d) delta 7.97 (d, j=1.9 hz, 1H), 7.85 (d, j=1.7 hz, 2H), 7.72 (d, j=8.4 hz, 1H), 7.62 (dd, j=8.4, 1.8hz, 1H), 7.57-7.47 (m, 3H), 7.35-7.27 (m, 2H), 7.26-7.18 (m, 1H), 6.99 (d, j=8.4 hz, 1H), 6.60 (dt, j=15.2, 3.7hz, 1H), 6.34 (dt, j=15.2, 0.9hz, 1H), 4.36 (p, j=3.8 hz, 1H), 4.15 (t, j=5.3 hz, 2H), 3.35 (td, j=3.7, 1.27 (m, 1.h), 6.26-7.18 (m, 1H), 6.34 (d, j=8.4 hz, 1H), 6.60 (dt, j=15.9 hz, 1H), 4.34 (j=3.3.9 hz, 1H). 556 (M) ⁺ +1).

Example 2: synthesis of Compound I-2

Synthesis of Compound 2 As in example 1, only the starting compound c was replaced with

And (3) obtaining the product.

Step one: synthesis of Compound 3

To a solution of compound 1 (344 mg,0.47 mmol) in N, N-dimethylformamide (15 mL) were added potassium hydroxide (105.5 mg,1.88 mmol) and elemental iodine (239 mg,0.94 mmol), the reaction was allowed to react at room temperature for 3 hours, TLC was monitored to complete the reaction, saturated sodium sulfite solution was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), washed with water (20 mL. Times.2), dried over anhydrous sodium sulfate with saturated salt (20 mL) and concentrated column chromatography was performed to obtain iodo compound 2 (162 mg, 40%). MS (ESI, m/z): 860 (M) ⁺ +1).

Step two: synthesis of Compound 4

To a deuterated acetic acid solution (4 mL) of compound 3 (154 mg,0.18 mmol) was added sodium acetate (49 mg,0.36 mmol), and the mixture was allowed to react for 24 hours at room temperature, followed by completion of TLC detection, concentration under reduced pressure, and separation and purification by column chromatography to give compound 4 (46 mg, 35%). MS (ESI, m/z): 734 (M) ⁺ +1).

Step three: synthesis of Compound I-2

The synthesis method is as in example 1, and only the corresponding raw materials need to be replaced. ¹ H NMR(500MHz，Chloroform-d)δ7.97(d，J＝1.9Hz，1H)，7.85(d，J＝1.7Hz，2H)，7.72(d，J＝8.4Hz，1H)，7.62(dd，J＝8.4，1.8Hz，1H)，7.57-7.47(m，3H)，7.35-7.27(m，2H)，7.26-7.18(m，1H)，6.99(d，J＝8.4Hz，1H)，6.60(dt，J＝15.2，3.7Hz，1H)，6.34(dt，J＝15.2，0.9Hz，1H)，4.36(p，J＝3.8Hz，1H)，4.15(t，J＝5.3Hz，2H)，3.35(td，J＝3.7，1.0Hz，2H)，3.20(td，J＝5.3，4.1Hz，2H)，2.92(s，6H)，2.53(q，J＝9.0Hz，2H).MS(ESI，m/z)：551(M ⁺ +1).

Example 3: synthesis of Compound I-3

The synthesis method is as in example 2, and the raw material compound 2-1 is only required to be replaced by the compound 2. 1HNMR (500 mhz, chloride-d) delta 7.97 (d, j=1.9 hz, 1H), 7.85 (d, j=1.7 hz, 2H), 7.72 (d, j=8.4 hz, 1H), 7.62 (dd, j=8.4, 1.8hz, 1H), 7.57-7.47 (m, 3H), 7.35-7.27 (m, 2H), 7.26-7.18 (m, 1H), 6.99 (d, j=8.4 hz, 1H), 6.60 (dt, j=15.2, 3.7hz, 1H), 6.34 (dt, j=15.2, 0.9hz, 1H), 4.36 (p, j=3.8 hz, 1H), 4.15 (t, j=5.3 hz, 2H), 3.35 (td, j=3.7, 1.3 hz), 20.20 hz, 1H), 6.60 (dt, j=15.9 hz, 1H), 6.36 (tm, 3.7hz, 1H). 557 (M) ⁺ +1).

Example 4: anti-proliferative activity assay of test compounds for expression of wild-type and mutant ERalpha breast cancer cells

Cell antiproliferative activity was detected using CTG luminescence. ATP is an essential factor for maintaining normal cell vital activity, is a key index of metabolism of living cells, and can truly reflect the state and number of living cells. During the test, cellTiter-gloTM reagent is added to the culture medium, and the luminescence value is measured and is proportional to the ATP content, so that the number of living cells can be detected by measuring the ATP content. The cells used were MCF7-WT and MCF7-Y537S cells.

The specific experimental operation steps are as follows:

1. compound configuration:

1) Compounds were formulated using DMSO to a storage concentration of 10 mM;

2) The compounds were diluted twice at the highest concentration point at 10mM top dose (100% DMSO) for ten points, two duplicate wells were set for each concentration;

3) The compound was diluted 100-fold using the cell-corresponding medium to give a compound concentration of 100. Mu.M top dose (1% DMSO).

2. Cell plating:

1) Cell plating density was 5000cells/well, cell plating was performed overnight, and the volume was 20. Mu.L;

2) To a 96-well plate, 20. Mu.L of test compound was added, 40. Mu.L of each well, and the final concentration of top dose of compound was 50. Mu.M (0.5% DMSO). After the completion of the dosing, incubation was carried out at 37℃for 72h with 5% CO 2.

3. Cell detection: 20. Mu. LCTG reagent was added to each well and incubated for 20min for detection using the program Luminescence.

4. And (3) data processing: calculation of IC using Graphpad software ₅₀ Values.

Table 1 antiproliferative activity (IC) of test compounds against wild-type and mutant breast cancer cells _s0 nM)

Names of Compounds	MCF7-WT	MCF7-Y537S
			I-1	0.26	1.8
I-2	0.28	2.0
			I-3	0.21	1.9
H3B-6545	0.72	4.5

As shown in Table 1, the compounds I-1 to I-3 have remarkable inhibitory activity on wild-type and mutant breast cancer cells and are superior to the positive control H3B-6545.

Example 5: test compound pharmacokinetic property detection

Male SD rats were selected for oral (10 mg/kg) or intravenous (2 mg/kg) administration, 5min,15min,30min,1h,2h,4h,8h,10h,24h after the administration, blood was continuously taken from the ocular fundus venous plexus and placed in an EP tube containing heparin, centrifuged, and upper plasma was taken for LC-MS/MS analysis, and pharmacokinetic parameters were calculated using WinNonlin software according to the blood concentration-time data obtained from the test, and oral bioavailability was calculated.

The research result shows that the oral bioavailability of BHV-3500 in rats is 36%, and the half-life period is 2.5h; and the oral bioavailability of the compound I-1 is improved to 75%, and the half life is prolonged to 6.8h.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims (10)

1. A compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having the structure:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ Or R is ₇ Independently selected from the group consisting of hydrogen and deuterium,

at the same time, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ Or R is ₇ At least one of which is deuterium.

2. The compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, according to claim 1, wherein the compound is represented by any of the following structural formulas:

3. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to claims 1-2, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or adjuvant.

4. Use of a compound of formula I as defined in claims 1-2, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition as defined in claim 3, for the preparation of a selective estrogen receptor covalent antagonist.

5. The use according to claim 4, wherein the estrogen receptor is estrogen receptor α.

6. The use according to claim 5, wherein the estrogen receptor α is a wild type estrogen receptor α or a mutant estrogen receptor α.

7. Use of a compound of formula I as defined in claims 1-2, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition as defined in claim 3, for the manufacture of a medicament for the prophylaxis and/or treatment of cancer.

8. The use according to claim 7, wherein the cancer is breast cancer, preferably estrogen receptor positive breast cancer, more preferably from wild type estrogen receptor alpha positive breast cancer, mutant estrogen receptor alpha positive breast cancer.

9. The use according to claim 7, wherein the cancer is a cancer associated with abnormal estrogen receptor activity.

10. The use according to claim 9, wherein the cancer associated with aberrant estrogen receptor activity is selected from the group consisting of cancer associated with aberrant wild-type estrogen receptor α activity, and cancer associated with aberrant mutant estrogen receptor α activity.